Interstitial fibrosis represents a key pathological process in non-alcoholic steatohepatitis (NASH). In the liver, fibrogenesis is primarily mediated by activated hepatic stellate cells (HSCs) transitioning from a quiescent state in response to a host of stimuli. The molecular mechanism underlying HSC activation is not completely understood. Here we report that there was a simultaneous up-regulation of PIAS4 expression and down-regulation of SIRT1 expression accompanying increased hepatic fibrogenesis in an MCD-diet induced mouse model of NASH. In cultured primary mouse HSCs, stimulation with high glucose activated PIAS4 while at the same time repressed SIRT1. Over-expression of PIAS4 directly repressed SIRT1 promoter activity. In contrast, depletion of PIAS4 restored SIRT1 expression in HSCs treated with high glucose. Estrogen, a known NASH-protective hormone, antagonized HSC activation by targeting PIAS4. Lentivirus-mediated delivery of short hairpin RNA (shRNA) targeting PIAS4 in mice ameliorated MCD diet induced liver fibrosis by normalizing SIRT1 expression in vivo. PIAS4 promoted HSC activation in a SIRT1-dependent manner in vitro. Mechanistically, PIAS4 mediated SIRT1 repression led to SMAD3 hyperacetylation and enhanced SMAD3 binding to fibrogenic gene promoters. Taken together, our data suggest SIRT1 trans-repression by PIAS4 plays an important role in HSC activation and liver fibrosis.

Ginsenoside Re (Re) is the main component of Zhenyuan Capsule (ZYC), which was wildly used in clinic in China for adjunctive treatment of coronary heart disease (CHD) and type II diabetes (T2DM). Nonalcoholic fatty liver disease (NAFLD) is one of the most important complications of T2DM, as well as an important risk factor of CHD. The aim of the present study was to investigate the effects of Re on NAFLD in db/db mice, one of the most recognized gene deficient animal models on T2DM. Sixteen db/db mice and sixteen wild-type mice were divided into four groups and orally administered Re or placebo in equal volume. According to the results, Re showed no obvious effect on blood glucose, lipids, or body weight of db/db mice. Histology pictures of hepatic tissue showed that Re did not improve steatosis, too. However, some evidence suggested that hepatic injury in db/db mice was attenuated by Re administering. Collagen deposition and aminotransferase elevation were significantly downregulated in the DB+Re group compared to those in the DB Group. The mechanisms of the protect effects of Re represented in db/db mice with NAFLD might be inhibiting oxidative stress and the reupregulation of peroxisome proliferator-activated receptor γ (pparγ) expression. The results of this study indicated that ZYC might be able to help T2DM patients with NAFLD to control the progress of NAFLD as an alternation of thiazolidinediones, synthetic agonists of PPARγ, whose side effects and adverse events should not be ignored.

Chinese herbal medicine is widely used because it has a good safety profile and few side effects. However, the risk of adverse drug reactions caused by herb-drug interactions (HDIs) is often overlooked. Therefore, the task of identifying possible HDIs and elucidating their mechanisms is of great significance for the prevention and treatment of HDI-related adverse reactions. Since extract fromDioscorea bulbiferaL. rhizomes (DB) can cause various degrees of liver damage, it is speculated that HDIs may occur between DB extract and chemicals metabolized or excreted by the liver. Our study revealed that the cardiotoxicity of pirarubicin (THP) was increased by co-administration of DB, and the expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) in the liver was inhibited by DB extract, which led to the accumulation of THP in heart tissue. In conclusion, there are risks of the co-administration of DB extract and THP. The mechanism of HDIs can be better revealed by targeting the efflux transporters.

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Cancer is one of the leading causes of death worldwide, and with the continuous development of life sciences and pharmaceutical technology, more and more antitumor drugs are being used in clinics to benefit cancer patients. However, the incidence of chemotherapy-induced cardiotoxicity has been continuously increasing, threatening patients’ long-term survival. Cardio-oncology has become a research hot spot, and the combination of nanotechnology and biomedicine has brought about an unprecedented technological revolution. Nanomaterials have the potential to maximize the efficacy and reduce the side effects of chemotherapeutic drugs when used as their carriers, and several nano-formulations of frequently used chemotherapeutic drugs have already been approved for marketing. In this review, we summarize chemotherapeutic drugs that are highly associated with cardiotoxicity and evaluate the role of nano-delivery systems in reducing cardiotoxicity based on studies of their marketed or R&D nano-formulations. Some of the marketed chemotherapy drugs are combined with nano-delivery systems that can effectively deliver chemotherapy drugs to tumors and cannot easily penetrate the endothelial barrier of the heart, thus decreasing their distribution in the heart and reducing the cardiotoxicity to some extent. However, many chemotherapy nanomedicines that are marketed or in R&D have not received enough attention in determining their cardiotoxicity. In general, nanomedicine is an effective method to reduce the cardiotoxicity of traditional chemotherapy drugs. However, cardiovascular complications in cancer treatment are very complex diseases, requiring the application of multiple measures to achieve effective management and prevention.

Diabetic cardiomyopathy (DCM), one of the most severe complications of diabetes, is closely associated with oxidative stress (OS) in its development and progression. Studies have shown that plant antioxidants play an important role in the prevention and treatment of DCM by modulating redox signaling and regulating the sources of reactive oxygen species (ROS) generation. However, most existing evidence comes from animal and cellular experiments, and clinical data are limited. In addition, their clinical application faces challenges, including poor bioavailability and difficulty in standardizing active ingredients. Therefore, this review focuses on the role of plant antioxidants in regulating myocardial oxidative stress and maintaining redox homeostasis, and explores their potential clinical applications and current limitations. This review aims to provide a theoretical basis and guidance for the prevention and treatment of DCM using plant antioxidants.